Mitochondrial Replacement Therapy

Mitochondrial Replacement Therapy: Is this the Beginning of the End?

By Lilah Connell

How much value should and do humans place on being natural? In today’s increasingly technological world humans now more than ever have the ability to transform the world and themselves through various medical procedures, but to what extent should this occur? With Mitochondrial Replacement Therapy, a controversial new form of assisted reproductive technology, women with mutated mitochondrial DNA will be able to have a biological child without the threat of mitochondrial diseases. While the benefits of this procedure are clear, there could be serious ramifications on what humans regard as natural. Is it unethical to deny women the freedom to have biological children by not legalizing this procedure? Or do the potential effects on human nature and the physical nature of the human body outweigh the ethical justification of Mitochondrial Replacement Therapy regarding women’s desires to reproduce?  These considerations will lead to a conclusion regarding the ethics of the legalization of Mitochondrial Replacement Therapy based on the value of nature.

Table of Contents

• Introduction
• Scientific and Historical Background of Mitochondrial Replacement Therapy
• Conceptions of Nature
• Natural Desires and Human Nature
• Nature of the Human Body/Genetics
• Conclusion

Two years after giving birth to their first child, Lori and Neil Martin received devastating news that their son, Will, has a rare genetic disorder known as Leigh’s disease caused by a mutation in his mitochondrial DNA that he had inherited from his mother. They were told it is very unlikely that Will will live past his seventh birthday and that soon his disease would cause his cells to die and eventually shut down his whole body. While Lori and Neil would like to have more children they realize it is very unlikely that they could have a child that does not suffer from a similar condition. As of now they are focused on trying to give Will the best life they can and cherishing their moments with him. When asked her opinion on Mitochondrial Replacement Therapy, a controversial new form of assisted reproductive technology that could create embryos by replacing mutated mitochondria with donor mitochondria to create a healthy human being, Lori Martin said: “it’s not in my timeline. But the fact that other women might have that opportunity, I just think that’s an incredibly meaningful gift,” (Moisse, Texas Boy Battles Rare Leigh’s Disease). As evident with this case, Mitochondrial Replacement Therapy, or MRT, has the potential to save lives, but at what costs to the nature of human beings? How much value should and do humans place on being natural? In today’s increasingly technological world humans now, more than ever, have the ability to transform the world and themselves through various medical procedures, but to what extent should this occur? With Mitochondrial Replacement Therapy women with mutated mitochondrial DNA will be able to have biological children without the threat of mitochondrial diseases. While the benefits of this procedure are clear, there could be serious ramifications to what humans regard as natural. Is it unethical to deny women the freedom to have biological children by not legalizing this procedure? Or do the potential effects on human nature and the physical nature of the human body outweigh the ethical justification of Mitochondrial Replacement Therapy regarding women’s desires to reproduce?  These considerations will lead to a conclusion regarding the ethics of the legalization of Mitochondrial Replacement Therapy based on the value of nature.

Mitochondrial DNA and Diseases

Every human cell contains two sets of DNA: mitochondrial DNA and nuclear DNA. Mitochondrial DNA is located on mitochondria found in the cytoplasm of cells. Its shape is a circular double helix, and it contains 37 genes, 13 of which function solely to code for proteins. The remaining genes provide the instructions for making transfer RNA and ribosomal RNA used in protein synthesis to help combine amino acids into proteins. Proteins have many important functions in our bodies, including movement, growth, and protection of immune systems. Mitochondria are often referred to as the powerhouse of the cell and are frequently compared to a battery as its common function is releasing energy for the cell to use. However, recent studies are contradicting this with claims that mitochondria are much more than the battery of the cell. There have even been statements that mitochondrial DNA plays a role in the characteristics of a human being (Cussins, The Collapse of a Dangerous Analogy). Mitochondrial DNA inheritance is strictly maternal, meaning that all of the inherited mtDNA is transferred through the cytoplasm in the ovum. In addition, mitochondrial DNA does not undergo recombination. Recombination is the process of forming new alleles in offspring by exchanging genetic materials between the DNA of the mother and the father. Therefore only the mother’s mitochondrial DNA will be passed down to the resulting child. The only way the mitochondrial DNA can vary is through mutation. If these mutations occur in a female, they will then be passed on to the future generations, which will likely cause a mitochondrial disease to develop.

Mitochondrial diseases are diseases caused by a mutation in mitochondrial DNA that can appear at any time in a person’s life. A mutation is a permanent change in DNA. This often changes the behavior of a cell, but the degree to which a mutation can affect a human being varies. Mutations often occur when DNA is being replicated and can be in the form of an insertion, when extra base pair(s) is added into the gene sequence, a deletion, in which portions of the DNA are lost, or substitutions, where base pairs are changed to another base pair. The symptoms of mitochondrial disease can include deafness, blindness, muscle weakness, cognitive impairments, heart, lung, and kidney failure, diabetes, and death. Because the symptoms of the disease can range from manageable and not life threatening  to fatal, it is impossible to judge whether or not this procedure should be allowed for families with a certain severity of the disease, especially considering that the symptoms can also range from mother to child. This is why the mother may only experience a small symptom that enables her to live a mostly normal life while her child risks being severely sick such as in the case of Lori and Will Martin. Currently about 1 in 4,000 children and adults are diagnosed with mitochondrial diseases, but because the symptoms of mitochondrial disease are so varied, misdiagnosis is common and doctors believe the statistics are actually much higher. Mitochondrial diseases are prevalent and affect many individuals and families, so a treatment or prevention would be greatly beneficial.

Mitochondrial Replacement Therapy Procedures

There are three different possible procedures that have the potential to prevent a child from inheriting mutated mitochondria, while but maintaining the nuclear DNA from its intended social parents. Each of the three procedures are forms of Mitochondrial Replacement Therapy that begin with the use of in vitro fertilization, or IVF, in which an egg is fertilized in a laboratory outside of the human body. Prior to IVF, eggs and sperm must be collected from the intended social parents as well as eggs from a third woman who will share the same mitochondrial DNA as the resulting child. Because the resulting child has nuclear DNA from its intended social parents as well as mitochondrial DNA from the egg donor the child will have three genetic parents. The term social parent means the parents that are going to raise and care for the child. A social parent is not always the biological parent, so the mitochondrial donor would not be considered a social parent, but would be biologically related to the child. In this case, however, the social parents would also be biological parents.

The most commonly accepted and well known procedure is known as maternal spindle transfer. During maternal spindle transfer, the nuclei from both eggs are removed and the nucleus of the donor egg is replaced with the nucleus of the intended social mother’s egg. The egg now contains nuclear DNA from the social mother and mitochondrial DNA from the egg donor. It is then fertilized with the father’s sperm and implanted into the mother. This procedure is considered the least controversial of the three because it only harms human ova, the female reproductive cell, not zygotes, the first complete cell of an embryo, which some people consider to be human beings. Embryo destruction may be considered unethical by some people; however I am not focusing on the ethics surrounding this aspect of MRT.

Another procedure known as pronuclear transfer begins with the fertilization of an egg from the egg donor, which contains healthy mitochondrial DNA. An egg from the intended social mother is also fertilized. This embryo contains mutated mitochondria, and would result in a child with mitochondrial diseases if it was implanted. The nuclei are then removed from both embryos and a new embryo is created by transferring the nucleus (including the nuclear DNA) from the embryo containing the mutated mitochondria into the embryo containing the cytoplasm and healthy mitochondria of the egg donor.

The third and final form of Mitochondrial Replacement Therapy, known as embryo cell nuclear transfer, is very similar to pronuclear transfer. In this procedure only one embryo is created using the sperm and egg of the intended social parents. Then the nucleus is removed from the embryo and placed in a new donor egg (with its nucleus removed) that contains healthy mitochondria. This egg is then fertilized and implanted for development. Because all of the different procedures result in a child with mitochondrial DNA from the donor and nuclear DNA from the social mother and father, the child resulting from the procedures will have DNA from three different people and therefore have three genetic parents.

History and Current Status of Mitochondrial Replacement Therapy

Another form of assisted reproductive technology that is very similar to Mitochondrial Replacement Therapy known as cytoplasmic transfer was occurring in the United States from the later 1990s until 2001. In 2001 the procedure was shut down by the Food and Drug Administration due to risks to the resulting children after 17 babies had been born and it was discovered that one had autism and another was missing a chromosome. Although it was later discovered to be a way to prevent mitochondrial diseases, cytoplasmic transfer was used to cure infertility in older or infertile women. A majority of the clinical trials were occurring in New Jersey and were carried out by injecting the cytoplasm of a donor egg into an infertile woman’s egg before in vitro fertilization occurred.

In the United States the FDA is currently debating whether or not to allow clinical trials to carry out Mitochondrial Replacement Therapy. The Cellular, Tissue, and Gene Therapies Advisory Committee of the United States FDA met on February 25, 2014 to discuss the safety of the procedure, however they did not discuss the legal or other ethical implications. On January 27, 2015 a newly formed committee known as the Institute of Medicine held their first meetings in what is expected to be a series of meetings to further discuss the possible legalization of Mitochondrial Replacement Therapy (Cussins, FDA Intensifies Discussions on Medical and Ethical Issues of Mitochondrial Replacement Therapy). The United Kingdom is much farther along in their discussions of Mitochondrial Replacement Therapy than the United States. The United Kingdom had a ban on all germline manipulation, but a panel formed in 2011 to discuss making MRT an exception to this rule. This procedure was being so strongly advocated for because it would be “the only way to circumvent mitochondrial conditions to enable women to have genetic children,” (Medscape, FDA Considers Mitochondrial DNA Replacement). On February 4, 2015 the United Kingdom’s House of Commons legalized MRT with a vote of 382 to 128. However, “some scientists and nongovernmental organizations have argued that not enough is known about possible side effects of the technique to go forward in human patients,” (Vogel and Stokstad, U.K. Parliament Approves Controversial Three-Parent Mitochondrial Gene Therapy). Therefore there is still much controversy surrounding MRT, even where it is legal. Despite critics, MRT is now regarded as safe for human trials. However, just because something is safe it does not mean that it is ethical or the right thing to do. Therefore it is important that the FDA considers all aspects of Mitochondrial Replacement Therapy before making a decision, including how it affects our conception of what is natural.

In order to accurately judge whether or not Mitochondrial Replacement Therapy is ethical on the grounds of the value of nature, the different perceptions of human nature must first be identified. It is important to recognize that there is no one, correct, conception of human nature and that it can vary from person to person. There are however more commonly accepted and believed perceptions of human nature that I will explore here.

The first conception is that human nature is to be creative and transform the world and ourselves using our knowledge and skills to contribute to the world and build upon the achievements of previous humans. It is our responsibility as inhabitants of the world to do everything in our power to improve it. People who have this perspective of human nature often feel that new technologies, such as MRT, should be used to better the world and humanity. They feel if we are not transforming the world then our existence has no purpose, so we must take advantage of our time on earth and the new resources and ideas that emerge during it. However, the second conception of human nature strongly opposes the first.

The second conception is that humans are simply thrown into being whatever it is that we are and that it is our job to affirm nature as it is because none of us created ourselves. It is our duty to leave the world as we found it and live in nature the way it was given to us because that is the way it was meant to be. This conception emphasizes the idea that the purity of the world holds a special value that humans should not infringe upon but rather embrace. People who hold these moral beliefs on nature most likely feel that MRT and other new technologies should not be pursued as it would be a violation of nature to alter the world and its people in this permanent way. Their belief of being thrown into being strongly conflicts with the “manipulation” involved in MRT.

I think that humans ought not to seek to change the world in a way in which there is a large possibility the impact of their actions would be negative, but I do not feel that humans should accept that the world is at its best without our influence and that we should not be innovative for the sake of nature. To me this is a sad outlook on life that should not be embraced. I think that it is a large part of human nature to form opinions and to want to have these opinions and beliefs heard by other people. Humans should feel that they have the ability to create a positive change. Without this belief, some people may feel that there is no incentive to live. However, I also agree with the second conception’s idea of certain things having a sacred value that should not be interfered with. While I do not agree that these certain sacred things are humans and the world in general, I think that it is healthy to believe that there are certain things in life that should not be intervened with. For example, to a certain extent humans should try to refrain from interfering with wildlife and their environments unless their motives are purely for the benefit of the species. To look at the world and think that everything can and should be better could also be a sad outlook on life.

If MRT is not legalized, some women could feel that they are being denied the freedom to have biological children. Therefore, I feel that the natural desires of human beings must be taken into account. Because a desire is often thought of as something we want rather than need, it is sometimes dismissed as unnecessary, but what happens when this desire becomes so strong that it becomes a necessity for someone to achieve a full life? An example of this would be the desire to sustain your life, the desire for food or water comes naturally to people. They are without thought and essential for humans. I think that the desire to have a biological child is a natural desire that for some women cannot be controlled. However, there are people who do not believe that humans have a natural desire to reproduce at all.

There are a lot of people who do not have children, some of which probably never wanted to have children. This is not to say that something is wrong with these people, but rather that this natural desire is perhaps stronger in other individuals. It could also be that society has conditioned humans in a certain way. Reproducing is the way we sustain life on the earth, and it is often a goal of humans to reproduce. Some people may look at it is a way to pass on the family name and leave their mark on the earth. The idea of motherly and fatherly instinct is a good example of an instinctive trait of people that everyone possesses but it is clear that certain individuals have a stronger protective instinct than others. Every person is different, and there are different factors in people’s lives that may cause their desire to reproduce to be stronger or very weak. I do not think it would be accurate to state that because some people do not want to have children that there is no natural drive within humans to reproduce.

People for Mitochondrial Replacement Therapy argue that desires for a genetically related child are natural and therefore unable to be suppressed and out of their control. Marni Falk, a mitochondrial specialist, accurately summarized this claim through the statement:  “There’s an enormous drive to reproduce—that’s just within us. I think it’s unfair to put that on people with mitochondrial disease, that they shouldn’t have that drive or desire,” (Tingley, The Brave New World of Three Parent I.V.F). On the other hand, people against this procedure not only argue that the safety of the procedure is not guaranteed, but also feel that a natural desire does not validate such an alteration to the human body as it goes against their belief in accepting the world and humans the way it has been given to us. Therefore opinions regarding Mitochondrial Replacement Therapy depend heavily upon people’s different perceptions of nature and personal desires. However, these ideas can also be connected to some of the technology and resources that are already legal and in use by humans.

Resources Humans Already Use

There are other forms of assisted reproductive treatments in which parents choose to spend large amounts of money and accept the risks of the procedures all in order to have a genetic child. However, we are comfortable offering these procedures, despite the fact that they will ultimately result in the same outcome: parents taking advantage of technology to have a biological, healthy child.

Pre-implantation genetic diagnosis, or PGD, is often used to select from multiple embryos an embryo with or without certain diseases. Therefore, parents that have a heritable disease that will likely be passed down to their child greatly benefit from this technology. However, this procedure is not very effective for mitochondrial diseases because of the way it is inherited from mother to child. In MRT on the other hand, embryos are altered which causes a child with the same nuclear DNA, but different mitochondrial DNA to result as the child that would have been born without MRT. The degree to which this change in mitochondrial DNA would affect the phenotype of the child, if at all, is unknown. The alteration of embryos is a large difference from PGD; however the idea that natural desires should be taken into consideration and pursued is present in both procedures as they allow couples to have genetic children who wouldn’t be able to without it.

Parents play a large role in shaping their children to be who they are. It is widely known that parents are always trying to make their children better, including smarter, healthier, or more attractive in order to give them the best possible life. While some parents do this more so than others, it is normal for parents to spend time, money, and effort on helping their children achieve the best quality of life, which is often thought to stem from attractiveness and education. Therefore, humans already use their resources to improve upon themselves and their children, so is there anything wrong with using scientific technology to replace or reinforce resources we are already using?

There are differences between using MRT versus resources such as education and doctor’s appointments to shape the life of a child as these methods are not only more widely used, uncontroversial, and often required by the law, but they are also viewed as small modifications. A modification is the act of making changes to something without altering its essential nature or character (Oxford English Dictionary). MRT can be considered a change to the nature of the human being and would therefore be more than a small modification.

The Case of Alana Saarinen

Alana Saarinen is one of the seventeen people created through the use of cytoplasmic transfer when the clinical trials in the United States were still being carried out. She is currently fifteen years old and healthy. Her mother, Sharon Saarinen had an injection of cytoplasm in Michigan in 2000 when she was 36 years old after struggling with infertility. The clinical trial she participated in, run by Dr. Michael Fikah, was not specifically for mothers with mutated mitochondria. However, there are varying opinions on who this procedure should be available to as it is also found to be a treatment for infertility as in this case, but others feel that this procedure should only be offered to women with mutated mitochondria.

This case is a good example of how strong and overwhelming the natural desire to have a biological child can be. When discussing her life prior to using MRT, Sharon stated: “I felt worthless. I felt guilty that I couldn’t give my husband a child…When you want a biological child but you can’t have one, you’re distraught. You can’t sleep, its 24-7, constantly on your mind,” (Rawle, Meet the schoolgirl with THREE parents). Her feelings clearly show the emotional distress and pain that being unable to have a biological child can cause women. This needs to be taken into account when considering whether or not natural desires are enough to justify MRT or even be a factor in the decision regarding the procedure.

When considering the natural desires and immense drive of human beings to reproduce, it appears only ethical to ensure that every human being has the opportunity to do so.  We, as humans, cannot possibly satisfy the desires of everyone, but these desires must be heard and valued. Specifically regarding the natural desire to have a biological child I think it is important to recognize that there are some people who do not have the opportunity to have their own children whether it is due to financial, medical, or other reasons, but that to offer a procedure to those who would then be able to have a biological child would be as Lori Martin put it “an incredibly meaningful gift.”

Alternatives to Mitochondrial Replacement Therapy

There are alternatives to Mitochondrial Replacement Therapy that would allow couples to have healthy children, however neither of these options would fulfill the mother and in one case the father’s desire to have a genetically related child. One alternative would be for couples to purchase an egg from a donor, similar to how they would if Mitochondrial Replacement Therapy was available, and fertilize the donor egg with the father’s sperm without any genetic manipulation and implant it into the mother. The second alternative would be to adopt a child. A common and very valid argument is that a child is a child, genetically linked or not, and being a parent is not about genetics. While this is a popular belief that I agree with, the idea being explored is whether or not humans should use MRT based on the “laws of nature.”

The overarching question that we have to ask ourselves is: how much value do we, and should we place on being natural when it comes to our bodies in today’s society? While considering the value of a natural human body the definition of natural is most likely not changed by humans, which reflects the conception of affirming nature. The growing technological world has increased people’s acceptance of makeup, cosmetic surgeries, and other technologies that encourage people to change their physical appearance or inner composition without a medical necessity to do so. While considering the two different conceptions of human nature, either transforming or affirming the world, there are very different opinions on whether it is acceptable to adapt our value of nature to the growing technological world.

One of the biggest controversies within this procedure is the fact that it is a germline therapy. A germline therapy is a procedure in which the permanent alterations made to the body would be passed down to all future generations, and would therefore alter the genetics of all future humans from starting from the human who received the treatment. People against these techniques argue that it is playing God by tampering with human nature and crosses a line that cannot be taken back. In addition, the permanence of this procedure will forever change the nature of more than just the people giving consent to the procedure. “Michael Sandel argues that using gene transfer technologies to enhance ourselves or our children represents ‘a Promethean aspiration to remake nature, including human nature, to serve our purposes and satisfy our desires,’” (Kaebnick, Nature, Human Nature, and Biotechnology). For many people there is comfort in having boundaries and knowing that at a certain point something cannot go any further. People are afraid of germline therapies because of this fear of what is on the other side of the “boundary”. No other germline therapies are currently being carried out, so MRT would be unknown territory. However, there is a strong counter argument that advocates the use of germline therapy on the basis that it justifies the usefulness of a procedure as it would permanently eliminate the risk of inheritance of mitochondrial diseases within that germline, unless another mutation occurs. People with this belief feel germline therapies are a risk worth taking because the benefits would be enormous.

While eugenics would be an extreme, it is a risk that must be considered while discussing the ethics of a germline therapy such as Mitochondrial Replacement Therapy. Eugenics is the idea of using science to alter humans in a way that creates supreme, ultimate beings through controlled breeding of desired traits. Because a germline therapy affects the genetics of all future generations it would be much easier for eugenics to occur with this type of procedure. Because of the idea that mitochondria is simply the powerhouse of the cell, many people believe that this procedure cannot lead to eugenics as the mitochondria do not function to code for our traits. However, the role of mitochondrial DNA is disputed and therefore there is a chance that its effect is larger than previously thought. Even if mitochondrial DNA does turn out to just be the battery of the cell there is still concern that this could be the beginning of use of reproductive technology to engineer embryos, a frightening thought in today’s society where uniqueness is largely encouraged.

The combination of the fact that Mitochondrial Replacement Therapy is a germline procedure and that it results in a child with three genetic parents makes this procedure appear as anything but natural. Often times natural is thought of as whatever is normal, and having three peoples’ DNA in one person is certainly not normal in today’s society. This factor is what makes MRT so unique, but is also a factor that scares people and further complicates the life of the being created. Just the thought of having three genetic parents is hard for people to understand, and it would certainly be a factor that makes the child feel different from other children. Identity issues are also a concern for a child born with three genetic parents as a result of MRT. It can be difficult for people to understand the role of the third parent, which includes whether they are even going to be considered a third parent in this first place.

Another form of assisted reproductive technology comparable to MRT is surrogacy. This procedure is legal in the United States and involves three people, two women and one man, to create one child. Therefore as a result of the procedure it is possible for the resulting child to have three parents. In a traditional surrogacy case the surrogate mother would not be biologically related to the child, however she would be the child’s gestational mother because she carried the child throughout its development. Then the child would have two biological parents that contributed egg and sperm and will often also be the child’s social parents. In mitochondrial replacement therapy all three of the parents would have a genetic relationship with the child to some degree. However, the three parent idea is not completely foreign territory to people. This brings into question the role of genetics within a family and what it means to be a parent, which warrants further discussion.

The definition of nature, the value of nature, and the strength of natural desires can differ drastically between people. This does not make one person right or wrong, but rather that nature means different things to different people. This means that some people could view MRT as a large violation of nature as it involves the physical change of the nature of humans permanently. Whereas others may view the legalization of MRT as a very natural thing to do as it promotes humans to create, develop, and transform the world as well as encourages the natural desire to reproduce.

Based on my personal beliefs regarding nature, which is that humans should aspire to be transformative and that human nature is ultimately what drives people to be who they are and do what they do, I think it would be unethical to deny women with mutated mitochondria or women suffering from infertility the freedom to have biological children. I think that humans are naturally inclined to want to reproduce and to deny this procedure to women who feel this way could be emotionally unbearable. However, safety is always a priority, which is why I feel that closely regulated clinical trials on humans should begin, allowing people to ease in to the effects of MRT. With the recent legalization of MRT in the United Kingdom, it is safe to believe that the procedure has been thoroughly tested (trials were conducted on monkeys) and that it will be safe for humans. However, I think there should be some limitations on MRT. For example a minimum age requirement to ensure that the parents are mature enough to have a child. In addition, because I feel that all women have a freedom to have biological children, I feel that it is only ethical to allow all women who either have mutations in their mitochondria or are infertile to use this procedure as MRT has been known to treat infertility. The world is constantly changing as new people, ideas, and technology emerge whether we approve of it or not, and I think it is natural to embrace the changes that we cannot control.

The questions and considerations I have made throughout my paper connect to many other technologies humans currently use or are possibly on the horizon. For example, cosmetic surgeries were and still are a topic of great debate as they involve humans altering the nature of their bodies in order to appear a certain way. An even greater dispute surrounds a new process known as de-extinction, which is the process of reviving extinct species. In each of these circumstances humans must be able to step back and ask themselves: what is nature and how can we determine where the line should be drawn between what is and is not natural in today’s increasingly technological world?